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The SAR study of 6,8-disubstituted quinoline derivatives as anti cancer agents

Year 2017, , 152 - 159, 01.06.2017
https://doi.org/10.18663/tjcl.292058

Abstract

Aim:
In this study, determination of the anticancer potentials
of 6,8-disubstituted quinolines, mechanisms of their action and effects of
different substituents to anticancer activity were aimed.

Material
and Methods:
Reaction of
tetrahydroquinoline (
1) with molecular bromine (Br2) and then
aromatization of product afforded 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6,8-dibromoTHQ,
2) and 6,8-dibromoquinoline (6,8-diBrQ, 3). These compounds were
converted to corresponding derivatives 6,8-dimethoxyquinoline (6,8-diMeOQ,
4),
6,8-dicyanoquinoline (6,8-diCNQ,
6) and 6,8-diphenylquinoline
(6,8-diPhQ,
5) via nucleophilic substitution and Suzuki cross coupling
reactions. BrDU cell proliferation, LDH cytotoxcity, DNA laddering and DNA
Topoisomerase I inhibition assays were applied to synthesized compounds (
2-6)
against HeLa, HT29 and C6 cell lines to determine their anti cancer potentials.

Results: Although only 2 and 5 have
antiproliferative effect against against HeLa
(Human Cervix Carcinoma) and C6 (Rat Brain Tumor Cells) cell lines, compounds 2, 3, 4 and
5
inhibited the proliferation of HT29
(Human Colorectal
Adenocarcinoma)
cell line. Moreover, 6,8-dibromoTHQ 2 showing significant inhibition against all cell
lines did not showed cytotoxic effect. However, compound
2 have caused
DNA fragmantation and inhibited Topoisomerase I enzyme. 







Conclusion:
The exchange of functional groups of quinoline
skeleton at C-6 and C-8 positions have caused different anticancer activities. The
potential of being anticancer agents of
6,8-DibromoTHQ 2
and 6,8-diphenylquinoline
5 were
investigated d
ue to exhibition of their
antiproliferative and apoptotic effects.

References

  • 1. Manfred H. Alkaloids: Nature's Curse or Blessing? 1st Edition. Weinheim, Wiley-VCH; 2002.
  • 2. Poon CY, Chiu P, A synthesis of the tetracyclic carboskeleton of isaindigotidione. Tetrahedron Lett 2004; 45: 2985-8.
  • 3. Jacquemond-Collet I, Benoit-Vical F, Valentin A, et al. Antiplasmodial and cytotoxic activity of galipinine and other tetrahydroquinolines from Galipea officinalis. Planta Med 2002; 68: 68-9.
  • 4. Fang KC, Chen YL, Sheu J, et al. Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J Med Chem 2000; 43: 3809-12.
  • 5. Palit P, Paira P, Hazra A, et al. Phase transfer catalyzed synthesis of bisquinolines: Antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation. Eur J Med Chem 2009; 44: 845-53.
  • 6. Jampilek J, Dolezal M, Kunes J, et al. Investigating the antiproliferative activity of quinoline-5,8-diones and styrylquinolinecarboxylic acids on tumor cell lines. Med Chem 2005; 1: 591.
  • 7. Musiol R, Jampilek J, Buchta V, et al. Antifungal properties of new series of quinoline derivatives. Bioorg Med Chem 2006; 14: 3592-8.
  • 8. Ökten S, Çakmak O, Erenler R, et al. Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities. Turk J Chem 2013; 37: 896-908.
  • 9. Ökten S, Şahin ÖY, Tekin Ş, et al. In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines. J Biotechn 2014; 185: S106.
  • 10. Zouhiri F, Danet M, Benard C, et al. HIV-1 replication inhibitors of the styrylquinoline class: Introduction of an additional carboxyl group at the C-5 position of the quinoline. Tetrahedron Lett 2005; 46: 2201-5.
  • 11. Şahin A, Çakmak O, Demirtaş İ, et al. Efficent and selective synthesis of quinoline derivatives. Tetrahedron 2008; 64:10068-74.
  • 12. Broch S, Aboab B, Anizon F, et al. Synthesis and in vitro antiproliferative activities of quinoline derivatives. Eur J Med Chem 2010; 45: 1657-62.
  • 13. Mphahlele MJ, Lesenyeho LG. Halogenated Quinolines as Substrates for the Palladium-Catalyzed Cross-Coupling Reactions to Afford Substituted Quinolines. J Heterocycl Chem 2013; 50: 1-16.
  • 14. Solomon VR, Lee H. Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 2009; 625: 220-33.
  • 15. Shi A, Nguyen TA, Battina SK, et al. Synthesis and anti-breast cancer activities of substituted quinolines. Bioorg Med Chem Lett 2008; 18: 3364-8.
  • 16. Ökten S, Erenler R, Köprülü TK, et al. In vitro antiproliferative/cytotoxic activity of 2,3'-biindole against various cancer cell lines. Turk J Biol 2015; 39: 15-22.
  • 17. Şahin ÖY, Ökten S, Tekin Ş, et al. Determination of anticancer activities of some quinoline derivatives against C6 tumor cells. J Biotechn 2012; 161: S24.
  • 18. Köprülü TK, Tekin Ş, Ökten S, et al. Detection of mechanism and anticancer activity of the new quinoline compounds MC20 and MC21. J Biotechn 2014; 185: S93.
  • 19. Ökten S, Çakmak O. Synthesis of Novel Cyano Quinoline Derivatives. Tetrahedron Lett 2015; 56: 5337-40.
  • 20. Ökten S, Eyigün D, Çakmak O. Synthesis of Brominated Quinolines. Sigma J Eng Nat Sci 2015; 33: 8-15.
  • 21. Çakmak O, Ökten S, Tekin Ş. Bromlanmış Metoksi, Siyano ve Nitro/amino Kinolin Türevlerinin Seçici-Etkin Sentezleri ve Biyolojik Aktivitelerinin İncelenmesi, 2014, 112T394 Nolu Tübitak Projesi, Sonuç Raporu.
  • 22. Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem 1994; 218: 314-9.

6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması

Year 2017, , 152 - 159, 01.06.2017
https://doi.org/10.18663/tjcl.292058

Abstract

Amaç:
Bu çalışmada, 6,8-disübstitüe kinolin türevlerinin
antikanser potansiyelleri, etki mekanizmaları ve farklı sübstituentlerin
aktiviteye etkilerinin belirlemesi amaçlanmıştır.

Gereç ve Yöntemler: Tetrahidrokinolin molekülü (1), moleküler
brom (Br2) ile reaksiyonu ve müteakiben aromatlaştırılması ile 6,8-dibromo-1,2,3,4-tetrahidrokinolin
(6,8-dibromoTHQ, 2) ve 6,8-dibromokinolin (6,8-diBrQ, 3) elde
edildi. Bu moleküller, yer değiştirme ve Suzuki Kenetleme reaksiyonları sonucu ile
6,8-dimetoksikinolin (6,8-diMeOQ, 4), 6,8-disiyanokinolin (6,8-diCNQ, 6)
ve 6,8-difenilkinolin’e (6,8-diPhQ, 5) dönüştürüldü. Sentezlenen bileşiklerin
(2-6) antikanser potansiyellerinin ortaya çıkartmak için HeLa (İnsan
rahim kanser hücresi), HT29 (Kolon kanseri) ve C6 (Sıçan beyin kanser hücresi) hücre
hatlarına karşı BrDU hücre proliferasyonu, LDH sitotoksisite, DNA bantlaşma ve DNA Topoizomeraz I inhibisyon testleri
uygulandı.

Bulgular: HT29 hücre hatlarında ise, bileşikler 2,
3, 4 ve 5 numaralı bileşikler hücre proliferasyonunu
inhibe etmiştir fakat HeLa ve C6 hücre hatlarında sadece 6,8-dibromoTHQ 2 ve 6,8-diPhQ 5 bileşikleri önemli derecede antiproliferatif etki göstermiştir. 6,8-dibromoTHQ 2, tüm hücre hatlarında yüksek inhibisyon gösterirken, sitotoksik etki göstermemiştir.
6,8-dibromoTHQ 2 DNA bantlaştırma ve Topoizomeraz I enziminin inhibe
edebilme özelliği ortaya çıkarılmıştır.







Sonuçlar: Kinolin halkasının C-6 ve C-8 konumlarında
fonksiyonel grupların değiştikçe farklı aktiviteleri gözlenmiştir. 6,8-DiBrTHQ 2 ve 6,8-diPhQ 5
moleküllerinin antiproliferatif ve apoptotik aktivite göstermeleri sebebiyle
antikanser ajan olma potansiyelleri belirlenmiştir. 

References

  • 1. Manfred H. Alkaloids: Nature's Curse or Blessing? 1st Edition. Weinheim, Wiley-VCH; 2002.
  • 2. Poon CY, Chiu P, A synthesis of the tetracyclic carboskeleton of isaindigotidione. Tetrahedron Lett 2004; 45: 2985-8.
  • 3. Jacquemond-Collet I, Benoit-Vical F, Valentin A, et al. Antiplasmodial and cytotoxic activity of galipinine and other tetrahydroquinolines from Galipea officinalis. Planta Med 2002; 68: 68-9.
  • 4. Fang KC, Chen YL, Sheu J, et al. Synthesis, antibacterial, and cytotoxic evaluation of certain 7-substituted norfloxacin derivatives. J Med Chem 2000; 43: 3809-12.
  • 5. Palit P, Paira P, Hazra A, et al. Phase transfer catalyzed synthesis of bisquinolines: Antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation. Eur J Med Chem 2009; 44: 845-53.
  • 6. Jampilek J, Dolezal M, Kunes J, et al. Investigating the antiproliferative activity of quinoline-5,8-diones and styrylquinolinecarboxylic acids on tumor cell lines. Med Chem 2005; 1: 591.
  • 7. Musiol R, Jampilek J, Buchta V, et al. Antifungal properties of new series of quinoline derivatives. Bioorg Med Chem 2006; 14: 3592-8.
  • 8. Ökten S, Çakmak O, Erenler R, et al. Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities. Turk J Chem 2013; 37: 896-908.
  • 9. Ökten S, Şahin ÖY, Tekin Ş, et al. In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines. J Biotechn 2014; 185: S106.
  • 10. Zouhiri F, Danet M, Benard C, et al. HIV-1 replication inhibitors of the styrylquinoline class: Introduction of an additional carboxyl group at the C-5 position of the quinoline. Tetrahedron Lett 2005; 46: 2201-5.
  • 11. Şahin A, Çakmak O, Demirtaş İ, et al. Efficent and selective synthesis of quinoline derivatives. Tetrahedron 2008; 64:10068-74.
  • 12. Broch S, Aboab B, Anizon F, et al. Synthesis and in vitro antiproliferative activities of quinoline derivatives. Eur J Med Chem 2010; 45: 1657-62.
  • 13. Mphahlele MJ, Lesenyeho LG. Halogenated Quinolines as Substrates for the Palladium-Catalyzed Cross-Coupling Reactions to Afford Substituted Quinolines. J Heterocycl Chem 2013; 50: 1-16.
  • 14. Solomon VR, Lee H. Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 2009; 625: 220-33.
  • 15. Shi A, Nguyen TA, Battina SK, et al. Synthesis and anti-breast cancer activities of substituted quinolines. Bioorg Med Chem Lett 2008; 18: 3364-8.
  • 16. Ökten S, Erenler R, Köprülü TK, et al. In vitro antiproliferative/cytotoxic activity of 2,3'-biindole against various cancer cell lines. Turk J Biol 2015; 39: 15-22.
  • 17. Şahin ÖY, Ökten S, Tekin Ş, et al. Determination of anticancer activities of some quinoline derivatives against C6 tumor cells. J Biotechn 2012; 161: S24.
  • 18. Köprülü TK, Tekin Ş, Ökten S, et al. Detection of mechanism and anticancer activity of the new quinoline compounds MC20 and MC21. J Biotechn 2014; 185: S93.
  • 19. Ökten S, Çakmak O. Synthesis of Novel Cyano Quinoline Derivatives. Tetrahedron Lett 2015; 56: 5337-40.
  • 20. Ökten S, Eyigün D, Çakmak O. Synthesis of Brominated Quinolines. Sigma J Eng Nat Sci 2015; 33: 8-15.
  • 21. Çakmak O, Ökten S, Tekin Ş. Bromlanmış Metoksi, Siyano ve Nitro/amino Kinolin Türevlerinin Seçici-Etkin Sentezleri ve Biyolojik Aktivitelerinin İncelenmesi, 2014, 112T394 Nolu Tübitak Projesi, Sonuç Raporu.
  • 22. Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem 1994; 218: 314-9.
There are 22 citations in total.

Details

Subjects Health Care Administration
Journal Section Orıgınal Artıcle
Authors

Salih Ökten 0000-0001-9656-1803

Osman Çakmak This is me

Şaban Tekin This is me

Publication Date June 1, 2017
Published in Issue Year 2017

Cite

APA Ökten, S., Çakmak, O., & Tekin, Ş. (2017). 6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması. Turkish Journal of Clinics and Laboratory, 8(4), 152-159. https://doi.org/10.18663/tjcl.292058
AMA Ökten S, Çakmak O, Tekin Ş. 6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması. TJCL. December 2017;8(4):152-159. doi:10.18663/tjcl.292058
Chicago Ökten, Salih, Osman Çakmak, and Şaban Tekin. “6,8-Disübstitüe Kinolin analoglarının Anti Kanser Ajanlar Olarak Yapı Aktivite (SAR) çalışması”. Turkish Journal of Clinics and Laboratory 8, no. 4 (December 2017): 152-59. https://doi.org/10.18663/tjcl.292058.
EndNote Ökten S, Çakmak O, Tekin Ş (December 1, 2017) 6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması. Turkish Journal of Clinics and Laboratory 8 4 152–159.
IEEE S. Ökten, O. Çakmak, and Ş. Tekin, “6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması”, TJCL, vol. 8, no. 4, pp. 152–159, 2017, doi: 10.18663/tjcl.292058.
ISNAD Ökten, Salih et al. “6,8-Disübstitüe Kinolin analoglarının Anti Kanser Ajanlar Olarak Yapı Aktivite (SAR) çalışması”. Turkish Journal of Clinics and Laboratory 8/4 (December 2017), 152-159. https://doi.org/10.18663/tjcl.292058.
JAMA Ökten S, Çakmak O, Tekin Ş. 6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması. TJCL. 2017;8:152–159.
MLA Ökten, Salih et al. “6,8-Disübstitüe Kinolin analoglarının Anti Kanser Ajanlar Olarak Yapı Aktivite (SAR) çalışması”. Turkish Journal of Clinics and Laboratory, vol. 8, no. 4, 2017, pp. 152-9, doi:10.18663/tjcl.292058.
Vancouver Ökten S, Çakmak O, Tekin Ş. 6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması. TJCL. 2017;8(4):152-9.


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